In the last decades a new class of highly potent biopharmaceutical drugs evolved. Antibody-Drug Conjugates (ADCs) or immune-conjugates are a new class of highly potent biopharmaceutical drugs. They are developed for the targeted cancer therapy and during the last decades they have received the utmost attention in the oncology field.
An ADC is a hybrid of two different worlds. On the one hand the conjugate consists of a monoclonal antibody targeting a tumor-specific antigen. To this biopharmaceutical antibody a highly potent small molecule, i.e. a cytotoxic agent is conjugated (sometimes also called payload or toxin). The monoclonal antibody and the small molecule are conjugated by covalent bonds via a linker fragment that allows chemical conjugation of the toxin molecule to the antibody. This fragment is (optionally) cleaved in target cells and the active toxin is released. Sometimes, a spacer, which may be another small molecule, is also used to increase the distance between antibody and a cytotoxic agent.
The main objective of ADC design and use is to combine the high cytotoxic potency of a small molecule and the high specificity of monoclonal antibody (mAb) for tumor-associated antigen targets. As the toxin is covalently bound to antibody and can be freed only after internalization in the cancer cell, the systemic toxicity is minimized. Due to its highly targeted tumor antigen recognition based on the antibody such conjugate allows excellent discrimination between healthy and cancer cells. In addition, based on the requirement of antigen binding for effective internalization and processing in cells, ADC drugs are expected to provide a wider therapeutic window compared to the cytotoxic agent alone.
Cytotoxic agents used as drug components for ADCs usually comprise 100 to 1000 times higher cytotoxic activity compared to conventionally applied chemotherapy drugs. Different classes of cytotoxic agents have been used for developing of ADCs. The use of Calicheamicins is for instance disclosed in U.S. Pat. No. 5,877,296 A. Maytansinoids are described in U.S. Pat. No. 7,276,497 B2, Monomethylauristatins in U.S. Pat. No. 7,659,241 B2 and Duocarmycins for instance in EP 2 948 183 B1.
The cytotoxic effect of anthracyclines is based on mechanism of action including:
1) intercalation of the anthracycline moiety into the DNA of the cell;
2) production of free radicals which react with DNA and other cellular macromolecules to cause damage to cell components or
3) interactions of the anthracycline drug molecules with the cell membrane.
The free radicals formed by reduction of the anthracycline can oxidize other molecules in the cell to produce formaldehyde, which in turn also reacts with DNA and amino group(s) present in anthracycline, forming covalently linked complex between anthracycline and DNA.
Some anthracyclines like for instance Doxorubicin or Daunorubicin have been widely used in the treatment of numerous cancers such as lung carcinoma, small cell lung cancer, leukemia, breast carcinoma, ovarian adenocarcinoma, different sarcomas and lymphomas, mesothelioma etc. Although anthracyclines belong to the most conventional chemotherapy drugs, most of well-known anthracyclines cannot be used as cytotoxic agents for ADCs. The reason is that the cytotoxic potency of the most common anthracyclines is too low to use them as ADC payload.
Therefore, it is the task of the present invention to provide a new class of anthracyclines comprising higher toxicity compared to state of the art anthracyclines and to provide a reliable route of synthesis to obtain such anthracyclines.